Feasibility and safety of 0.6% sodium alginate in endoscopic submucosal dissection for colorectal neoplastic lesion: A pilot study

Abstract Objectives The usefulness of 0.6% sodium alginate (SA) as a submucosal (SM) injection solution for endoscopic SM dissection (ESD) has gained attention over the past few years. However, using ESD for colorectal neoplastic lesions is not explicitly researched as yet. Thus, we conducted this study to determine the feasibility and safety of 0.6% SA solution for colorectal ESD. Methods In this single‐center, retrospective pilot study, a total of 100 cases treated with ESD using 0.6% SA as a SM injection solution for colorectal neoplasia at our institute were retrospectively reviewed to clarify the clinical feasibility and safety of 0.6% SA. The primary endpoint was to evaluate the complication rate, and the secondary endpoint was to determine the procedure time and the amount of solution used. Results Intraoperative perforation was observed in 1 case (1.0%), 2 cases (2.0%) presented with postprocedural hemorrhage, and no lethal adverse events were observed. The median ESD procedure times were 39.5 min (10–150), and the amount of solution used was less than 20 mL in 67 cases (67.0%). En‐bloc resection could be achieved in 97 cases (97.0%). Although six cases underwent subsequent surgery due to the deep SM invasion (>1000 μm), there were no cases with nodal involvement, confirmed through histopathological evaluation. Conclusions Our findings indicate that 0.6% SA can potentially ensure safe and secure ESD for colorectal neoplasia.

With the introduction of endoscopic submucosal (SM) dissection (ESD), the endoscopic resection of superficial colorectal neoplasia has recently shown remarkable advances.En-bloc resection can be achieved with ESD, even in large lesions greater than 20 mm in diameter, contributing to a lower local recurrence than piecemeal endoscopic mucosal resection. 3Patients who underwent ESD with completely resected lesions report no metastatic occurrence within 5 years postoperatively. 4urrently, 0.4% sodium hyaluronate (SH) is regarded as one of the most reliable and widely used solutions for ESD for colorectal neoplasia. 5However, perturbation of high-molecular-weight SH reportedly contributes to cancer aggressiveness via Hippo signaling activation, as confirmed through molecular biology research. 6H may stimulate the growth of residual tumor cells after endoscopic procedures such as ESD, followed by an upregulation of CD44 in murine models. 7Therefore, although 0.4% SH is a well-recognized and suitable SM injection solution for colorectal ESD, careful follow-up is required, particularly in cases with inadequate margins.Thus, a safer solution for SM injection is warranted for ESD.
Sodium alginate (SA) was extracted from algae for the first time in 1883 and has been used as a viscosityenhancing stabilizer and coagulator for food. 8,9SA has been used as a digestive mucosal protective agent at a concentration of 5% for over 60 years in Japan (Alloid G; Kaigen Pharma). 10 Thus, the efficacy and safety of SA are well established.2][13] A 0.6% SA solution (Liftal K; Kaigen Pharma Co.) for SM injection was approved in Japan in 2018.Although a randomized control study revealed that the efficacy rate of SM injection using 0.6% SA was noninferior to 0.4% SH in ESD for esophageal and gastric neoplastic lesions, the feasibility and safety of 0.6% SA in ESD for colorectal neoplastic lesions have not yet been clarified. 14Those backgrounds inspired us to conduct a single-center retrospective pilot study to evaluate the feasibility and safety of 0.6% SA solution for colorectal ESD.

Cases
We retrospectively reviewed 100 colorectal neoplasms treated with ESD using 0.6% SA at our institute between October 2019 and September 2021.All cases with colorectal neoplasia treated with ESD using 0.6% SA during the period were included in this study.Informed consent was obtained from all the patients included in this study.This study was approved by the institutional review board at Otaru Ekisaikai Hospital (IRB 21-07).

ESD procedure
ESD was conducted by eight colonoscopists (two with more than 15 years of experience and 6 with less than 15 years of experience), using a double-balloon endoscope (EI-580BT or EI-530B; FUJIFILM Co.) or an endoscope with a water jet (EC-580RD; FUJIFILM Co.), depending on the location of the lesions and the colonoscopists' choice.A solution of indigo carmine and epinephrine in glycerin-fructose (Glycerol; Taiyo Pharma Co., Ltd.) was first injected to lift the submucosa, and a mixed solution of indigo carmine and 0.6% SA was injected into the submucosa using a blunt needle (25 g, 3 mm in length, Top Corporation).Mucosal incision and SM dissection in all cases were conducted using a FlushKnife BT-S (1.5 mm, FUJIFILM Co.) and electrosurgical generator (VIO 300D; Erbe Elektromedizin).One of the typical cases is represented in Figure 1.

Study outcomes
As a pilot study, we evaluated the occurrence of adverse events, procedure time, and amount of injected solution treated with 0.6% SA.Perforation was defined as a hole visible during the procedure or free air detected with imaging tests, and post-procedural hemorrhage was defined as bleeding that required additional endoscopic treatment.The procedure time was defined as the time between the start of the mucosal incision and the completion of SM dissection.

RESULTS
Table 1 presents the clinical characteristics of the cases in this study.The median age and sex ratio (male/female) of cases were 71.5 (42-90) years and 60/40.Preoperatively, 15 cases were treated using antithrombotic agents (mono antiplatelet therapy; 7 cases, mono anticoagulant therapy; 7 cases, combination of antiplatelet and anticoagulant; 1 case).We suspended antithrombotic treatment prior to ESD, if possible.In this study, however, ESD was conducted without cessation in three cases, considering the underlying condition.The median diameter of lesions was 20 mm (6-50), and 41 cases (41.0%) were found in the ascending colon, followed by the transverse colon (19 cases),sigmoid colon (14 cases),rectum (11 cases), descending colon (10 cases), and cecum (5 cases).The number of cases with laterally spreading tumor non-granular type was 48 (48.0%), followed by laterally spreading granular tumor type (LST-G; 34 cases) and elevated type (18 cases).Seven cases out of 100 converted to snare resection during the ESD procedure (hybrid ESD) because of technical difficulties.Table 2 shows the postoperative findings of the cases investigated in this study.The median diameter of the resected specimen was 25 mm (10-60).Enbloc resection was performed in 97 cases (97.0%).Four cases resulted in an inconclusive horizontal margin on histopathological evaluation.There were no cases of lymphovascular invasion on histological evaluation.Furthermore, 6 cases (6.0%) underwent subsequent surgery due to the deep SM invasion (>1000 µm).Histological evaluation revealed no evidence of lymph node metastasis or residual tumor in all cases.Lethal adverse events were not observed in these cases.Intraoperative perforation was observed in 1 case (1.0%), and 2 cases (2.0%) presented with postprocedural hemorrhage, which required additional endoscopic treatment.The median procedure time was 39.5 min (10-150).Moreover, the volume of solution used was less than 20 mL in 67 cases (67.0%), 20-40 mL in 27 cases (27.0%), and more than 40 mL in 6 cases (6.0%).

DISCUSSION
In this pilot study, we suggested the feasibility and safety of ESD for colorectal neoplasia using 0.6% SA as a SM injection solution.Few cases present adverse events such as perforation and postprocedural hemorrhage.Furthermore, the median procedure time was acceptable, and the total volume of solution used was less than 20 mL (one vial) in more than half of the cases contributing to cost reduction.ESD for colorectal neoplasia is still considered a challenging procedure even for expert endoscopists in some situations, such as right-sided location, large tumor size, and high degree of fibrosis. 15Several characteristics, such as the winding, many folds, and thinness of the colonic wall, also cause the technical difficulties of colorectal ESD. 16Indeed, the perforation rate related to colorectal ESD is reportedly as high as 1.4%-20.4%,which is higher than that associated with stomach ESD. 17 Therefore, efficient SM elevation solutions are mandatory to maintain sufficient mucosal elevation and achieve safer ESD for colorectal neoplasia.In this study, the number of cases with perforation during the procedure was one (1.0%), and no cases presented post-procedural perforation.Furthermore, the number of cases with bleeding was two (2.0%) that could be well manageable only with endoscopic hemostasis.The rates of cases achieved en-bloc resection and negative resection margin were well acceptable (97 cases,97.0%;and 96 cases, 96.0%; respectively).Based on these findings, SA should be considered an SM injection solution for colorectal ESD.
There are several limitations to this study.First, the data used in this study was obtained from a single center.Furthermore, the long-term effects of 0.6% SA were not evaluated.As mentioned above, SH can potentially stimulate the growth of residual tumor cells after endoscopic procedures requiring close and long-term follow-up, particularly for patients with inadequate margins. 7In this regard, SA is likely to be safe and secure considering the ingredient, which needs further investigation.
In conclusion, our study revealed that 0.6% SA can potentially ensure a safe and secure ESD for colorectal neoplasia.Further investigations, including a high-quality prospective study to evaluate its noninferiority compared to existing solutions such as 0.4% SH or a long-term observational study to clarify the safety of 0.6% SA are warranted.

AC K N OW L E D G M E N T S
We are grateful to Dr. Harutaka Itaya (Itaya Gastroenterology Clinic in Otaru), who encouraged us to conduct the research through valuable advice and critical discussions.

C O N F L I C T O F I N T E R E S T S TAT E M E N T
Authors declare no conflicts of interests for this article.

F
I G U R E 1 A case representation of one of the cases enrolled in the study: (a) the 30 mm sized 0-Isp lesion was located in the sigmoid colon; (b) the endoscopic image during the submucosal dissection; (c) macroscopic view of the resected specimen; (d) the image of the lesion at the loupe statue (hematoxylin and eosin staining).